Advances in surgery and therapy for ovarian cancer have improved 5-year survival rates for the disease from 36% in the late 1970s to 44% in 2007. Although molecularly-targeted therapies have demonstrated remarkable efficacy against tumors in other disease sites, these therapies have been less effective against ovarian cancers, in part, due to sub-optimal potency/toxicity and adaptive resistance. Safe, effective, potent, and durable treatments for ovarian carcinoma are urgently needed. Combination therapies can overcome these challenges; however, optimally synergistic drug interactions require tight control of both cellular co-localization and delivery sequence/timing. These constraints can be challenging to meet using traditional formulations and delivery methods; however self-assembled layer-by-layer (LbL) polymer nanoparticle technologies are wellsuited, affording drug co-localization and precise control of delivery sequence/timing. Increasing evidence of the prevalence and therapeutic-significance of oncogenic ErbB3 signaling in ovarian carcinoma is rapidly emerging. This transmembrane receptor, constitutively activated in more than half of all tumor-derived cell lines, represents a singular therapeutic target for ovarian cancer, but perhaps more importantly, a prominent pathway for adaptive resistance to other therapies. We hypothesize that ErbB3-targeting combination therapies for ovarian cancer can be most safe and impactful when delivered using polymer nanotechnologies engineered to achieve intracellular release with optimally-identified combination, sequence, and timing. By integrating (a) high-throughput methods for analyzing gene expression, protein expression/signaling, toxicity, and therapeutic potential with (b) highly advanced cellular and animal models of ovarian carcinoma, we will identify synthetically lethal drug combinations and leverage newly-developed siRNA-incorporating LbL polymer nanotechnologies to recapitulate synergistic combination scheduling and delivery to patient-derived primary tumor xenograft models. These studies integrate a highly multidisciplinary team of biologists, engineers, chemists, and clinicians and seek to develop and accelerate the application of nanotechnologies for increasingly safe, effective, and durable combination therapies for ovarian cancer. The proposal will address 5 unmet needs in clinical therapy for advanced ovarian carcinoma: (i) the development of nanotechnologies that recapitulate optimal delivery sequence/timing of synthetically lethal drug combinations, (ii) the synergistic blockade of oncogenic ErbB3 signaling, (iii) the investigation of ErbB3 expression/signaling in the pathogenesis of fallopian-derived disease, (iv) the realization of robust/durable RNAi, and (v) the elucidation of resistance pathways/interventions for ErbB3-targteted combination therapies. We anticipate these findings to be directly relevant to the clinical translation of therapeutic nanotechnologies for recurrent and high-grade ovarian malignancies.